A36: Antidotes in Depth

INTRODUCTION

Silibinin is the active ingredient in milk thistle, Silybum marianum, purported to prevent and treat amatoxin induced liver failure. Legalon SIL is a purified silibinin derivative available via an FDA approved open treatment as an investigational new drug (IND) for IV administration in patients suspected of ingesting amatoxin containing mushrooms.

HISTORY

Milk thistle has been used since the 16th century for the treatment of liver disease. Legalon SIL has been used in Europe since 1984.

PHARMACOLOGY

Chemistry

Legalon SIL, silibinin-C-2′,3-dihydrogen succinate disodium salt (C₃₃H₂₈O₁₆Na₂) is a microcrystalline water soluble powder for injection manufactured by Rottapharm/Madaus, a German pharmaceutical company.⁴ Silibinin is a mixture of cis- and trans diastereomers of silibinin A and B extracted from milk thistle fruit and then esterified with succinic anhydride to form the water soluble salt.

Related Compounds

The extract from the seeds of the plant milk thistle (Silybum marianum) contains 65% to 80% silymarin. Silymarin contains many flavonoids ­including silybin A and silybin B, with a 1:1 ratio making up silibinin.¹³ Silymarin is poorly water soluble with a low bioavailability, but has substantial eneterohepatic cycling.

Mechanism of Action

Silibinin competitively inhibits the organic anion transporter (OATP1B3) that is responsible for the uptake and enterohepatic recycling of amatoxin. Early administration prevents initial uptake while later administration prevents enterohepatic recycling of the amatoxin.⁸ Other possible mechanisms of action include inhibition of hepatocyte TNF-α release, stimulation of mRNA protein synthesis, and antioxidant and antiinflammatory effects.

Pharmacokinetics and Pharmacodynamics

Legalon SIL is rapidly metabolized and eliminated from the blood. Precise details are not available.

ROLE IN AMANITA MUSHROOM EXPOSURE

There are no randomized clinical trials of Legalon SIL or silibinin in the treatment of amatoxin induced mushroom poisoning. Evidence for its use comes from observational studies in humans, a variety of animal studies with mixed results, and in vitro studies in cultured human hepatocytes.

Although in an experimental model of cultured canine hepatocytes silibinin was not able to reduce cytotoxicity, two experiments using cultured human hepatocytes demonstrated that the addition of silibinin was able to protect against lipid peroxidation and cytotoxicity, and also stimulate cell proliferation and attachment.^{5, 6, and 7}

One of the earliest animal studies was conducted in mice using sublethal doses of Amanita phalloides extract administered intraperitoneally (IP) every 24 hours for 3 doses.² Silymarin was administered intravenously (IV) at 16 and 24 hours, with the highest dose resulting in a 58% survival compared to 11% in the control group. When the experiment was repeated using a purified α-amatoxin, time ...